- Email: [email protected]
Towards therapeutic choices in ulcerative colitis
Comment
Towards therapeutic choices in ulcerative colitis only associated with depletion of T cells into the gut but could also induce a decrease in gut homing of antiinflammatory circulating cells. No difference in safety events was observed between patients who received PF-00547659 and those who received placebo. Gastrointestinal events have to be scrutinised because of the gut selectivity of MAdCAM and anti-integrin agents.7 A Clostridium difficile infection, an anal abscess, and an anal fistula were observed in patients treated with PF-00547659. Moreover, one patient with undiagnosed colorectal cancer at inclusion had a fulminant evolution and died 4 months later. Such safety signals on digestive complications will need particular attention as antibodies targeting lymphocyte trafficking into the gut are increasingly used in inflammatory bowel diseases. Additional safety data from large cohorts are now expected to better define the safety profile of this new therapeutic class. While these studies are ongoing, cautious screening for gut infections and colorectal neoplasia is recommended before patients are given an anti-integrin or anti-MAdCAM therapy.8 In TURANDOT, approximately half of patients had been previously treated with an anti-TNFα agent before inclusion. Remission rates with PF-00547659 were higher in treatment-naive patients than in those previously exposed to an anti-TNFα agent, with an absolute difference ranging from 7·5% to 16% among treatment groups. The same pattern has been observed with anti-integrins and tofacitinib in ulcerative colitis.5,9
www.thelancet.com Published online May 17, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31263-1
Published Online May 17, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31263-1 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)30930-3
Gastrolab/Science Photo Library
Within the past few decades ulcerative colitis has become a worldwide condition, with the highest prevalence reported in developed countries and increasing incidence in developing nations.1 5-aminosalicylic acid has remained the mainstay of treatment in approximately half of patients, although several options are now available for those who become intolerant or refractory to this firstline therapy. Beyond conventional treatments such as corticosteroids and thiopurines, antitumour necrosis factor (TNFα) blockers showed efficacy more than 10 years ago in patients with refractory ulcerative colitis.2 This first era of biological drugs has led to a therapeutic revolution in management of ulcerative colitis since it is associated with better survival without colectomy than before.3 Blocking trafficking of lymphocytes into the gut with antibodies that target adhesion molecules has also proved beneficial in placebo-controlled trials of patients with ulcerative colitis. Thus, antibodies targeting gut-homing α4β7 or αEβ7 integrins have shown efficacy in refractory ulcerative colitis, including in patients previously exposed to anti-TNFα treatment.4,5 Blockade of mucosal addressin cell adhesion molecule (MAdCAM), which binds the α4β7 integrin, should therefore be an effective therapeutic strategy for ulcerative colitis. In The Lancet, Séverine Vermeire and colleagues present results from a phase 2, randomised, doubleblind, placebo-controlled trial (TURANDOT) that assessed the efficacy and safety of PF-00547659, a subcutaneous anti-MAdCAM fully human monoclonal antibody, in 357 patients with moderate to severe ulcerative colitis.6 Patients with exclusive proctitis and those with an acute severe flare were excluded from the trial. Three of the four doses of PF-00547659 provided significantly higher remission rates than placebo at week 12 (including endoscopic remission defined as a Mayo endoscopic subscore of 0–1 by central reading). Only the highest dose was not more effective than placebo. Soluble MAdCAM measurements throughout the trial confirmed the biological effect of PF-00547659, showing mean suppression of 67–98%, which was more important at higher doses. As observed with etrolizumab, the biological effect of PF-00547659 was uncorrelated with its clinical effect.4 Mechanistic studies are required to explore whether blockade of the MAdCAM–α4β7 interaction at high levels is not
1
Comment
Conversely, there are no available data so far on the efficacy of anti-TNFα agents in patients who previously did not respond to anti-integrin therapy. In the coming years, physicians treating patients with refractory ulcerative colitis will have several therapeutic options with multiple modes of action, including anti-TNFα blockers, anti-adhesion molecules, JAK inhibitors, sphingosine-1-phosphate modulators, and faecal microbiota transplantation.2,10 In parallel with Crohn’s disease, the choice of the first line of biological agents in ulcerative colitis seems crucial. This choice is currently driven by indirect comparisons of efficacy and safety profiles, routes of administration, and costs. To help clinical guidance, head-to-head comparative trials and strategic studies are now needed to assess the best sequences and combinations of treatment. David Laharie Service d’Hépato-gastroentérologie, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, 33600 Pessac, Bordeaux, France [email protected]
1
Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46–54. 2 Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet 2017; 389: 1756–70. 3 Rungoe C, Langholz E, Andersson M, et al. Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979–2011. Gut 2014; 63: 1607–16. 4 Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699–710. 5 Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014; 384: 309–18. 6 Vermeire S, Sandborn WJ, Danese S, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis: the TURANDOT study. Lancet 2017; published online May 17. http://dx.doi.org/10.1016/ S0140-6736(17)30930-3. 7 Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut 2016; published online Feb 18. DOI:10.1136/gutjnl-2015-311079. 8 Fiorino G, Bonovas S, Cicerone C, et al. The safety of biological pharmacotherapy for the treatment of ulcerative colitis. Expert Opin Drug Saf 2017; 16: 437–43. 9 Feagan BG, Rubin DT, Danese S, et al. Efficacy of vedolizumab induction and maintenance therapy in patients with ulcerative colitis, regardless of prior exposure to tumor necrosis factor antagonists. Clin Gastroenterol Hepatol 2017; 15: 229–39. 10 Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017; 389: 1218–28.
I have received consulting fees from AbbVie, Janssen, MSD, Pfizer, and Takeda for work on ulcerative colitis and other related areas; and lecture fees and travel accommodations from AbbVie, Ferring, Janssen, MSD, Pfizer, Takeda, and Tillots.
2
www.thelancet.com Published online May 17, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31263-1
Towards therapeutic choices in ulcerative colitis only associated with depletion of T cells into the gut but could also induce a decrease in gut homing of antiinflammatory circulating cells. No difference in safety events was observed between patients who received PF-00547659 and those who received placebo. Gastrointestinal events have to be scrutinised because of the gut selectivity of MAdCAM and anti-integrin agents.7 A Clostridium difficile infection, an anal abscess, and an anal fistula were observed in patients treated with PF-00547659. Moreover, one patient with undiagnosed colorectal cancer at inclusion had a fulminant evolution and died 4 months later. Such safety signals on digestive complications will need particular attention as antibodies targeting lymphocyte trafficking into the gut are increasingly used in inflammatory bowel diseases. Additional safety data from large cohorts are now expected to better define the safety profile of this new therapeutic class. While these studies are ongoing, cautious screening for gut infections and colorectal neoplasia is recommended before patients are given an anti-integrin or anti-MAdCAM therapy.8 In TURANDOT, approximately half of patients had been previously treated with an anti-TNFα agent before inclusion. Remission rates with PF-00547659 were higher in treatment-naive patients than in those previously exposed to an anti-TNFα agent, with an absolute difference ranging from 7·5% to 16% among treatment groups. The same pattern has been observed with anti-integrins and tofacitinib in ulcerative colitis.5,9
www.thelancet.com Published online May 17, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31263-1
Published Online May 17, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31263-1 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)30930-3
Gastrolab/Science Photo Library
Within the past few decades ulcerative colitis has become a worldwide condition, with the highest prevalence reported in developed countries and increasing incidence in developing nations.1 5-aminosalicylic acid has remained the mainstay of treatment in approximately half of patients, although several options are now available for those who become intolerant or refractory to this firstline therapy. Beyond conventional treatments such as corticosteroids and thiopurines, antitumour necrosis factor (TNFα) blockers showed efficacy more than 10 years ago in patients with refractory ulcerative colitis.2 This first era of biological drugs has led to a therapeutic revolution in management of ulcerative colitis since it is associated with better survival without colectomy than before.3 Blocking trafficking of lymphocytes into the gut with antibodies that target adhesion molecules has also proved beneficial in placebo-controlled trials of patients with ulcerative colitis. Thus, antibodies targeting gut-homing α4β7 or αEβ7 integrins have shown efficacy in refractory ulcerative colitis, including in patients previously exposed to anti-TNFα treatment.4,5 Blockade of mucosal addressin cell adhesion molecule (MAdCAM), which binds the α4β7 integrin, should therefore be an effective therapeutic strategy for ulcerative colitis. In The Lancet, Séverine Vermeire and colleagues present results from a phase 2, randomised, doubleblind, placebo-controlled trial (TURANDOT) that assessed the efficacy and safety of PF-00547659, a subcutaneous anti-MAdCAM fully human monoclonal antibody, in 357 patients with moderate to severe ulcerative colitis.6 Patients with exclusive proctitis and those with an acute severe flare were excluded from the trial. Three of the four doses of PF-00547659 provided significantly higher remission rates than placebo at week 12 (including endoscopic remission defined as a Mayo endoscopic subscore of 0–1 by central reading). Only the highest dose was not more effective than placebo. Soluble MAdCAM measurements throughout the trial confirmed the biological effect of PF-00547659, showing mean suppression of 67–98%, which was more important at higher doses. As observed with etrolizumab, the biological effect of PF-00547659 was uncorrelated with its clinical effect.4 Mechanistic studies are required to explore whether blockade of the MAdCAM–α4β7 interaction at high levels is not
1
Comment
Conversely, there are no available data so far on the efficacy of anti-TNFα agents in patients who previously did not respond to anti-integrin therapy. In the coming years, physicians treating patients with refractory ulcerative colitis will have several therapeutic options with multiple modes of action, including anti-TNFα blockers, anti-adhesion molecules, JAK inhibitors, sphingosine-1-phosphate modulators, and faecal microbiota transplantation.2,10 In parallel with Crohn’s disease, the choice of the first line of biological agents in ulcerative colitis seems crucial. This choice is currently driven by indirect comparisons of efficacy and safety profiles, routes of administration, and costs. To help clinical guidance, head-to-head comparative trials and strategic studies are now needed to assess the best sequences and combinations of treatment. David Laharie Service d’Hépato-gastroentérologie, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, 33600 Pessac, Bordeaux, France [email protected]
1
Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46–54. 2 Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet 2017; 389: 1756–70. 3 Rungoe C, Langholz E, Andersson M, et al. Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979–2011. Gut 2014; 63: 1607–16. 4 Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699–710. 5 Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014; 384: 309–18. 6 Vermeire S, Sandborn WJ, Danese S, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis: the TURANDOT study. Lancet 2017; published online May 17. http://dx.doi.org/10.1016/ S0140-6736(17)30930-3. 7 Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut 2016; published online Feb 18. DOI:10.1136/gutjnl-2015-311079. 8 Fiorino G, Bonovas S, Cicerone C, et al. The safety of biological pharmacotherapy for the treatment of ulcerative colitis. Expert Opin Drug Saf 2017; 16: 437–43. 9 Feagan BG, Rubin DT, Danese S, et al. Efficacy of vedolizumab induction and maintenance therapy in patients with ulcerative colitis, regardless of prior exposure to tumor necrosis factor antagonists. Clin Gastroenterol Hepatol 2017; 15: 229–39. 10 Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017; 389: 1218–28.
I have received consulting fees from AbbVie, Janssen, MSD, Pfizer, and Takeda for work on ulcerative colitis and other related areas; and lecture fees and travel accommodations from AbbVie, Ferring, Janssen, MSD, Pfizer, Takeda, and Tillots.
2
www.thelancet.com Published online May 17, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31263-1